Enteral Tranexamic Acid Decreases Proteolytic Activity in the Heart in Acute Experimental Hemorrhagic Shock

Abstract

The mechanisms for cardiac injury after hemorrhagic shock (HS) are unresolved. We hypothesize that remote organ damage can be caused by uncontrolled pancreatic proteolytic activity, as enteral protease inhibition improves outcomes in experimental HS. Uncontrolled proteolysis in the heart may disrupt cardiac metabolism and adrenergic control with subsequent deleterious outcomes. To test this hypothesis, the heart rate–pressure product (RPP) as an index of myocardial oxygen consumption and the levels of fatty acid transporter proteins CD36 and FATP6 as surrogates for metabolic activity in the heart were measured in rats subjected to experimental HS (n = 6/group) with and without the enteral protease inhibitor tranexamic acid (TXA). Plasma troponin I and heart fatty acid-binding protein (HFABP) concentrations were measured as indices of myocardial damage. Expression of the adrenergic receptors β1, α1D, and β2 was also measured in the heart to determine the possible effects of shock with and without enteral TXA on the adrenergic control of heart function. Hemorrhagic shock was induced by reduction in mean arterial blood pressure to 35 mm Hg for 2 hours before reperfusion of shed blood. The RPP was maintained in shocked animals treated enterally with TXA but not in those subjected to HS alone; this group also demonstrated decreased HFABP and plasma troponin I levels. Serine protease (trypsin, chymotrypsin, and elastase) and matrix metalloproteinase (MMP)-2 and MMP-9 activity was elevated in cardiac tissue and plasma after HS and abrogated by enteral TXA. Levels of CD36, FATP6, β1, α1D, and β2 were also increased after HS in cardiac tissue, and the increases were mitigated by TXA treatment. These results suggest that increased proteolytic activity may contribute to cardiac injury after HS. Enteral TXA prevents these changes, indicating a potential therapeutic option in the management of shock with resultant cardiac injury.

Continuous enteral protease inhibition as a novel treatment for experimental trauma/hemorrhagic shock

“…Previous studies from our group demonstrated that enteral TXA has a protective function in the systemic circulation. Injury caused by shock to both the vasculature [17] and the heart [18] is mitigated and adrenergic receptor density in arterial smooth muscle and in the heart is preserved with this treatment and is concordant with the improvements in hemodynamics measured in the present study.…”

“…Hemorrhagic shock was induced using a standard fixedpressure Wiggers model, as described in previous studies [17,18]. Briefly, blood was slowly removed (0.5 ml/min) until a target mean arterial blood pressure of 40 mmHg was achieved.…”

“…In particular, both our rat and human studies point to the enhanced role of chymotrypsin-like, trypsin-like and elastase-like enzymes in shock [8,9]. Furthermore, hemodynamic stability, survival and recovery from experimental hemorrhage and other forms of shock are greatly improved following enteral administration of protease inhibitors such as tranexamic acid [16][17][18] as a possible countermeasure targeting pancreatic proteases in the small intestine, with the aim of inhibiting them before they reach the circulation. Hence, considering the implications of preclinical and clinical data pointing to the occurrence of dysregulated proteolysis and to the effectiveness of protease inhibition in the small intestine, it can be hypothesized that enhanced enzymatic activity is an additional pathophysiological mechanism characterizing circulatory shock, and should be targeted by appropriate treatments aimed to mitigate systemic protein degradation at the source i.e., in the bowel.…”